N-acetyl-l-cysteine (NAC) treatment is associated with reduced susceptibility to reinstatement of cocaine- seeking behavior in rats (Baker et al 2002) and with reduced cue-induced craving in cocaine-dependent human volunteers (LaRowe et al 2006). We propose these aims to evaluate the potential of NAC as a treatment for methamphetamine (MA) dependence: Specific Aim 1: To determine the effects of treatment with NAC (placebo, 1800 and 3600mg daily), compared to treatment with placebo, on cue- and MA-induced craving and MA subjective effects in non-treatment-seeking MA-dependent human volunteers. We hypothesize that treatment with NAC will reduce craving for MA reported following exposure to MA cues and will reduce craving and MA subjective effects reported following non-contingent administration of MA (0mg, 9mg, and 30 mg, IV). Specific Aim 2: To determine the effects of treatment with NAC (placebo, 1800 and 3600mg daily), compared to treatment with placebo, on the reinforcing effects of MA by measuring MA self-administration in non-treatment-seeking MA-dependent human volunteers. We hypothesize that treatment with NAC will reduce the number of choices made for MA during choice sessions. Fifteen participants will complete procedures during treatment with placebo, NAC 1800mg, and NAC 3600mg, using a within-subjects, double-blind, placebo-controlled design with at least 2 weeks separating each treatment episode. After 2 days of treatment with study medication, cue-induced craving will be assessed using visual analogue rating scales prior to and after exposing participants to MA and neutral cues using our newly developed virtual reality (VR) apparatus. Participants will then complete 2 sample sessions and 2 choice sessions, each occurring on a separate day. In sample sessions they will receive placebo, 9mg MA, and 30mg MA and subjective effects ratings will be collected. In 2 subsequent choice sessions participants will make a series of 10 choices between money and the drug available (placebo or MA) in that session. Any alterations in the reinforcing effects of MA associated with NAC treatment will be evident as changes in the number of choices made for MA. After discontinuation of study medication participants will be discharged, to return after at least 2 weeks until procedures have been completed during treatment with each dose of study medication. PUBLIC HEALTH RELEVANCE: N-acetyl-l-cysteine (NAC) treatment is associated with reduced susceptibility to reinstatement of cocaine-seeking behavior in rats and with reduced cue-induced craving in cocaine-dependent human volunteers. Therefore, we propose an exploratory/developmental clinical research study to evaluate the potential of NAC as a potential treatment in MA-dependent volunteers. This proposal is of considerable public health significance as it provides an initial evaluation of the therapeutic potential of a promising compound for the treatment of MA dependence, a disorder for which there no effective medication treatments currently exists.